This proposal describes a research program that I will develop at the start of my academic career; this program will investigate new and existing PET imaging biomarkers with high potential as a tool for detecting malignancies and monitoring response to therapy in breast cancer. This proposal is an extension of my training received previously and during the K99 mentoring period under the supervision of Drs. Jason Lewis, Jose Baselga and David Solit. The overall goal seeks to develop companion diagnostics for monitoring treatment of breast cancer that are resistant to targeted treatment due to induced feedback pathways. With multiple adaptive defense mechanisms stimulated as a consequence of therapy, the specific aim for the 3-year ROO award period seeks to develop immunoPET agent/s that target receptor tyrosine kinases EGFR and HER3 and demonstrate that these probes can measure pharmacologically triggered changes during targeted therapy of signaling pathways (i.e. PI3K/Akt, MEK and HER2). If proven successful, translation of this approach can ultimately provide clinicians with a perspective to continue or re-direct cancer management and treatment to an alternative regimen.